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Cancer immune control needs senescence induction by interferon-dependent cell cycle regulator pathways in tumours

Author

Listed:
  • Ellen Brenner

    (University of Tübingen)

  • Barbara F. Schörg

    (University of Tübingen)

  • Fatima Ahmetlić

    (Institut für Molekulare Immunologie, Helmholtz-Zentrum München
    Eigenständige Forschungseinheit Translationale Molekulare Immunologie, Helmholtz Zentrum München)

  • Thomas Wieder

    (University of Tübingen)

  • Franz Joachim Hilke

    (University of Tübingen)

  • Nadine Simon

    (University of Tübingen)

  • Christopher Schroeder

    (University of Tübingen)

  • German Demidov

    (University of Tübingen)

  • Tanja Riedel

    (Institut für Molekulare Immunologie, Helmholtz-Zentrum München)

  • Birgit Fehrenbacher

    (University of Tübingen)

  • Martin Schaller

    (University of Tübingen)

  • Andrea Forschner

    (University of Tübingen)

  • Thomas Eigentler

    (University of Tübingen)

  • Heike Niessner

    (University of Tübingen)

  • Tobias Sinnberg

    (University of Tübingen)

  • Katharina S. Böhm

    (University of Tübingen)

  • Nadine Hömberg

    (Institut für Molekulare Immunologie, Helmholtz-Zentrum München
    Eigenständige Forschungseinheit Translationale Molekulare Immunologie, Helmholtz Zentrum München)

  • Heidi Braumüller

    (University of Tübingen)

  • Daniel Dauch

    (University Hospital Tübingen
    German Cancer Research Consortium (DKTK), German Cancer Research Center (DKFZ))

  • Stefan Zwirner

    (University Hospital Tübingen)

  • Lars Zender

    (University Hospital Tübingen
    German Cancer Research Consortium (DKTK), German Cancer Research Center (DKFZ)
    Cluster of Excellence iFIT (EXC 2180) “Image Guided and Functionally Instructed Tumor Therapies”)

  • Dominik Sonanini

    (University of Tübingen
    University Hospital Tübingen)

  • Albert Geishauser

    (Institut für Molekulare Immunologie, Helmholtz-Zentrum München
    Eigenständige Forschungseinheit Translationale Molekulare Immunologie, Helmholtz Zentrum München)

  • Jürgen Bauer

    (University of Tübingen)

  • Martin Eichner

    (Institute of Clinical Epidemiology and Applied Biometry, University of Tübingen)

  • Katja J. Jarick

    (Würzburg University)

  • Andreas Beilhack

    (Würzburg University)

  • Saskia Biskup

    (Cluster of Excellence iFIT (EXC 2180) “Image Guided and Functionally Instructed Tumor Therapies”
    Center for Genomics and Transcriptomics (CeGaT) GmbH and Practice for Human Genetics)

  • Dennis Döcker

    (University of Tübingen
    Center for Genomics and Transcriptomics (CeGaT) GmbH and Practice for Human Genetics)

  • Dirk Schadendorf

    (German Cancer Research Consortium (DKTK), German Cancer Research Center (DKFZ)
    University Hospital, West German Cancer Centre, University Duisburg-Essen)

  • Leticia Quintanilla-Martinez

    (Cluster of Excellence iFIT (EXC 2180) “Image Guided and Functionally Instructed Tumor Therapies”
    Institute of Pathology, University of Tübingen)

  • Bernd J. Pichler

    (University of Tübingen
    Cluster of Excellence iFIT (EXC 2180) “Image Guided and Functionally Instructed Tumor Therapies”)

  • Manfred Kneilling

    (University of Tübingen
    University of Tübingen
    Cluster of Excellence iFIT (EXC 2180) “Image Guided and Functionally Instructed Tumor Therapies”)

  • Ralph Mocikat

    (Institut für Molekulare Immunologie, Helmholtz-Zentrum München
    Eigenständige Forschungseinheit Translationale Molekulare Immunologie, Helmholtz Zentrum München)

  • Martin Röcken

    (University of Tübingen
    German Cancer Research Consortium (DKTK), German Cancer Research Center (DKFZ)
    Cluster of Excellence iFIT (EXC 2180) “Image Guided and Functionally Instructed Tumor Therapies”)

Abstract

Immune checkpoint blockade (ICB)-based or natural cancer immune responses largely eliminate tumours. Yet, they require additional mechanisms to arrest those cancer cells that are not rejected. Cytokine-induced senescence (CIS) can stably arrest cancer cells, suggesting that interferon-dependent induction of senescence-inducing cell cycle regulators is needed to control those cancer cells that escape from killing. Here we report in two different cancers sensitive to T cell-mediated rejection, that deletion of the senescence-inducing cell cycle regulators p16Ink4a/p19Arf (Cdkn2a) or p21Cip1 (Cdkn1a) in the tumour cells abrogates both the natural and the ICB-induced cancer immune control. Also in humans, melanoma metastases that progressed rapidly during ICB have losses of senescence-inducing genes and amplifications of senescence inhibitors. Metastatic cells also resist CIS. Such genetic and functional alterations are infrequent in metastatic melanomas regressing during ICB. Thus, activation of tumour-intrinsic, senescence-inducing cell cycle regulators is required to stably arrest cancer cells that escape from eradication.

Suggested Citation

  • Ellen Brenner & Barbara F. Schörg & Fatima Ahmetlić & Thomas Wieder & Franz Joachim Hilke & Nadine Simon & Christopher Schroeder & German Demidov & Tanja Riedel & Birgit Fehrenbacher & Martin Schaller, 2020. "Cancer immune control needs senescence induction by interferon-dependent cell cycle regulator pathways in tumours," Nature Communications, Nature, vol. 11(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-14987-6
    DOI: 10.1038/s41467-020-14987-6
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